Novel interstitial therapy for immediate symptom relief and chronic therapy in interstitial cystitis

ABSTRACT

The present invention relates to a disorder of the lower urinary tract, and in particular, reducing the symptoms (including treatment) of interstitial cystitis in vivo. In a preferred embodiment, the present invention relates to treatment formulations and methods for reducing interstitial cystitis in patients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based on U.S. patent application Ser. No.11/045,411, filed on Jan. 27, 2005, now pending, which claims thebenefit of U.S. Provisional Application Ser. No. 60/540,186, all ofwhich are hereby incorporated by reference, in their entirety, into thisapplication, and from which priority is claimed.

FIELD OF THE INVENTION

The present invention relates to a disorder of the lower urinary tract,and in particular, reducing the symptoms (including treatment) ofinterstitial cystitis in vivo. In a preferred embodiment, the presentinvention relates to, treatment formulations and methods for reducinginterstitial cystitis in patients.

BACKGROUND OF THE INVENTION

Interstitial cystitis (IC) is a chronic progressive disorder of thelower urinary tract that causes urinary urgency and frequency and/orpelvic pain. For many years, urologists regarded IC as a rare diseasefor which they had no broadly effective treatment. In fact, thecondition is quite common. In 1999, prevalence in the United States wasestimated at 750,000 cases (Curhan, et al. J Urol 161(2):549-552(1999)). However the true prevalence of IC is estimated to be at least1-2 million patients who are suffering from severe chronic pelvic pain.

Treatments with dimethylsulfoxide (DMSO), approved for IC in 1977 on thebasis of data from uncontrolled trials, can be useful with weeklyintravesical instillations for 6 to 8 weeks then every two weeks for3-12 months for maintenance. However DMSO therapy results in benefit forapproximately 50% of IC patients treated and the treatment takes a longtime to reduce symptoms. Furthermore, this therapy causes pain that isunrelieved by local anesthetics by themselves due to their lack ofabsorption into the bladder wall. Narcotics are given for immediaterelief of symptoms however they are only minimally effective. Somepatients benefit from formal 8- to 12-week, one-on-one course ofbehavior modification. Patients are also advised to avoid potassium-richfoods, particularly citrus fruits, tomatoes, chocolate, and coffee.

Therefore, treatments that would both benefit a larger portion of thepatient population, provide immediate relief of symptoms without causingadditional pain, without requiring extensive alterations in diet, andfurther provide reversal of the disease process over time are necessary.The present invention meets that challenge by providing compositions,detection methods and novel IC management treatment methods with thebenefits described herein.

SUMMARY OF THE INVENTION

The present invention relates to a disorder of the lower urinary tract,and in particular, reducing the symptoms (including treatment) ofinterstitial cystitis in vivo. In a preferred embodiment, the presentinvention relates to treatment formulations and methods for reducinginterstitial cystitis in patients.

In some embodiments, the present invention provides treatmentformulations for reducing one or more of the following urinaryfrequency, urgency, and/or pelvic pain. In one embodiment, the presentinvention contemplates treating patients with interstitial cystitis(IC). While it is not intended that the present invention be limited toany particular form of IC, it is believed that the majority of ICpatients would benefit from this invention. In further embodiments, thepresent invention contemplates treating patients with any one or more ofthe following: urinary frequency, urgency, and/or pelvic pain.

In one embodiment, the present invention contemplates a compositioncomprising: a) a heparinoid, b) a local anesthetic, and c) a bufferingcompound. In one embodiment, the composition is in a solid state. In oneembodiment, the composition is in solution. In one embodiment, thecomposition is in solution, wherein said solution has a pH of at least7. In one embodiment, the composition is in solution, wherein saidsolution has a pH of at least 8. In one embodiment, the composition isin solution, wherein said solution has a pH from 7 to 12. Accordingly insome embodiments, the pH of said solution is at 7.0, 8.0, 9.0, 10.0,11.0, 12.0 (or any pH value between 7 and 12). The pH of the compositionis chosen to be near to the pKa of the local anesthetic.

In one embodiment, said composition comprises a heparinoid. Indeed avariety of heparins and related heparinoid compounds are contemplated,including, but not limited to one or more of the following: heparinsodium, pentosan polysulfate sodium, heparan sulfate, hyaluronic acid,chondroitin sulfate, glycosaminoglycans and the like. In one embodiment,said composition comprises at least 100 units of heparin per unit dose.In one embodiment, said composition comprises at least 10,000 units ofheparin per unit dose. In one embodiment, said composition comprisesfrom 10,000 to 40,000 units of heparin per unit dose. Accordingly insome embodiments, said composition comprises 100 units, 10,000 units,40,000 units (or any amount between 100 units and 40,000 units) ofheparin per unit dose. The present invention is not limited to anyparticular heparin. In one embodiment, said composition comprises from100 mg to 600 mg pentosan polysulfate sodium per unit dose. Accordinglyin some embodiments, said composition comprises 100 mg, 200 mg, 300 mg,400 mg, 500 mg, 600 mg (or any amount between 100 mg and 600 mg)pentosan polysulfate sodium per unit dose. The quantities for otherheparinoids can be chosen according to their activity by one of ordinaryskill in the art.

The present invention is not limited to any particular local anestheticor formulation. In some embodiments, the local anesthetic compriseslidocaine. Typically, the local anesthetic is selected from the groupconsisting of benzocaine, lidocaine, tetracaine, bupivacaine, cocaine,etidocaine, flecamide, mepivacaine, pramoxine, prilocalne, procaine,chloroprocaine, oxyprocaine, proparacaine, ropivacaine, dyclonine,dibucaine, propoxycaine, chloroxylenol, cinchocaine, dexivacaine,diamocaine, hexylcaine, levobupivacaine, propoxycaine, pyrrocaine,risocaine, rodocaine, and pharmaceutically acceptable derivatives andbioisosteres thereof. Preferably, the local anesthetic is selected fromthe group consisting of lidocaine, bupivicaine, benzocaine, tetracaine,etidocaine, flecamide, prilocalne, and dibucaine. More preferably, thelocal anesthetic is lidocaine.

In one embodiment, said buffering compound comprises sodium bicarbonate.The present invention is not limited to any particular bufferingcompound. Typically, the buffer is selected from the group consisting ofbicarbonate buffer, THAM or Tris (Tris(hydroxy ethyl)aminomethane)buffer, MOPS buffer (3-(N-morpholino)propanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADA(N-(2-acetamido)₂-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer,BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES(2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO(3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid)buffer, HEPPS(N-(2-hydroxyethylpiperazine)-N-(3-propanesulfonic acid),buffer, HEPPSO(N-(2-hydroxyethyl)piperazine-N-(2-hydroxypropanesulfonicacid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer,triethanolamine buffer, imidazole buffer, glycine buffer, ethanolaminebuffer, phosphate buffer, MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES(piperazine-N,N-bis(2-ethanesulfonic acid) buffer, POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid) buffer,TAPS(N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer;TAPSO (3-[N-tris(hydroxy ethyl)methylamino]-2-hydroxy-propanesulfonicacid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonicacid) buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer),2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanolbuffer. Preferably, the buffer is sodium bicarbonate buffer, Trisbuffer, phosphate buffer, MOPS buffer, or HEPES buffer.

In one embodiment, the present invention contemplates methods forreducing one or more of the following urinary frequency, urgency, and/orpelvic pain. In some embodiments, one or more of urinary frequency,urgency, and/or pelvic pain relates to interstitial cystitis (IC). Insome embodiments, the present invention contemplates methods forreducing interstitial cystitis in patients. In some embodiments, amethod for reducing symptoms of interstitial cystitis comprisesadministering any one of the above compositions to a subject. In someembodiments, a method for reducing symptoms of interstitial cystitiscomprises administering any one or more of an oral heparinoid incombination with any one of the above compositions to a subject. In someembodiments, said subject is human. In some embodiments, saidadministering comprises intravesical administration. In someembodiments, said administering comprises one or more of oral andintravesical administration. In some embodiments, said administeringfurther comprises a composition comprising 100 mg/day to 300 mg/daypentosan polysulfate sodium. In some embodiments, said administeringfurther comprises a composition comprising 100 mg/day to 600 mg/daypentosan polysulfate sodium.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows an exemplary embodiment of a PELVIC PAIN andURGENCY/FREQUENCY PATIENT SYMPTOM (PUF) SCALE.

FIG. 2 shows an exemplary embodiment of instructions for performing thePotassium Sensitivity Test (PST).

FIG. 3 (Table 1) shows an exemplary embodiment of how IC presents itselfin women and men.

FIG. 4 (Table 2) shows an exemplary embodiment of factors that canaffect the severity of an IC patient's symptoms on a given day.

FIG. 5 (Table 3) shows an exemplary embodiment of PUF Score as aPredictor of PST Result.

FIG. 6 (Table 4) shows an exemplary embodiment of a three-part treatmentregimen for IC.

FIG. 7 (Table 5) shows an exemplary embodiment of CME EducationalObjectives.

FIG. 8 (Table 6) shows an exemplary embodiment of Objectives for theClinician.

FIG. 9 shows Patient Overall Rating of Improvement of Symptoms used toassess response to treatment.

FIG. 10 shows the duration of relief of pain and urgency in 28 patientswith IC who received one intravesical instillation of therapeuticsolution containing 160 mg lidocaine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a disorder of the lower urinary tract,and in particular, the diagnosis of interstitial cystitis, and reducingthe symptoms (including treatment) of interstitial cystitis in vivo. Ina preferred embodiment, the present invention relates to compositionsand treatment formulations and methods for reducing interstitialcystitis in patients.

In the past, IC was regarded as a rare disease whose symptoms andprogression were difficult or impossible to control. It is now believedthat IC is a relatively common disorder in both women and men, and thatmost cases can be treated successfully. In the present invention,detection methods and a novel IC management treatment method thatutilizes different combinations of oral and intravesical agents aredescribed.

DEFINITIONS

To facilitate understanding of the invention, a number of terms aredefined below.

As used herein including within this specification and the appendedclaims, the terms “a,” “an” and “the” include both singular and pluralreferences, unless the content clearly dictates otherwise.

As used herein, the term “or” when used in the expression “A or B,” andwhere A and B refer to a composition, disease, product, etc., means one,or the other, or both.

The terms “chosen from A, B and C” and “chosen from one or more of A, Band C” are equivalent terms that mean selecting any one of A, B, and C,or any combination of A, B, and C.

As used herein, the term “comprising” when placed before the recitationof steps in a method means that the method encompasses one or more stepsthat are additional to those expressly recited, and that the additionalone or more steps may be performed before, between, and/or after therecited steps. For example, a method comprising steps a, b, and cencompasses a method of steps a, b, x, and c, a method of steps a, b, c,and x, as well as a method of steps x, a, b, and c. Furthermore, theterm “comprising” when placed before the recitation of steps in a methoddoes not (although it may) require sequential performance of the listedsteps, unless the content clearly dictates otherwise. For example, amethod comprising steps a, b, and c encompasses, for example, a methodof performing steps in the order of steps a, c, and b, the order ofsteps c, b, and a, and the order of steps c, a, and b, Unless otherwiseindicated, all numbers expressing quantities of ingredients, propertiessuch as molecular weight, reaction conditions, and so forth as usedherein, are to be understood as being modified in all instances by theterm “about.” Accordingly, unless indicated to the contrary, thenumerical parameters herein are approximations that may vary dependingupon the desired properties sought to be obtained by the presentinvention. At the very least, and without limiting the application ofthe doctrine of equivalents to the scope of the claims, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parametersdescribing the broad scope of the invention are approximations, thenumerical values in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains standarddeviations that necessarily result from the errors found in thenumerical value's testing measurements.

As used herein, “reducing,” and “reducing the symptoms of,” “reducinginterstitial cystitis,” and “reducing the symptoms of interstitialcystitis” refers to lowering, lessening and relieving of any one or moreof urinary urgency and frequency, and/or pelvic pain. In one embodiment,reducing interstitial cystitis may be determined by the patient. In oneembodiment, reducing interstitial cystitis may be determined by thephysician's evaluation. In one embodiment, reducing interstitialcystitis may be determined from comparing a PUF scale score to aprevious PUF scale score. In some embodiments, reducing interstitialcystitis is reducing symptoms in patients whose symptoms indicate, andare similar to, interstitial cystitis.

As used herein, “liquid” refers to a state of matter in which thesubstance has definite volume and takes the shape of the container (e.g.solution).

As used herein, “solution” refers to a mixture whose particles can beevenly distributed such that the relative concentrations of thecomponents are the same throughout (e.g. liquid, sol, and the like).

As used herein, “aqueous solution” and “water solution” refers to asolution in which water is the solvent.

As used herein, “therapeutic solution,” “therapeutical solution,” and“solution for reducing interstitial cystitis,” refers to any solutioncomprising known and potential therapeutic compounds.

As used herein, “pH” refers to a measure of effective concentration ofhydrogen ions in a solution (e.g. approximately related to the molarityof H⁺ by pH=−log [H⁺]).

As used herein, “solid” and “solid state” refers to a state of matter inwhich the substance has definite shape and volume (e.g. powder,crystals, beads, allomer, encapsulated substances, amorphous substancesand the like).

As used herein, the term “compound” refers to any chemical entity,pharmaceutical, drug, and the like that may or may not be used be usedto treat or prevent a disease, illness, sickness, or disorder of bodilyfunction.

As used herein, the term “therapeutic compounds” comprise both known andpotential therapeutic compounds.

As used herein, the term “known therapeutic compound” refers to acompound that has been shown (e.g., through animal trials or priorexperience with administration to humans) to be effective in suchtreatment or prevention.

As used herein, the term “therapeutic” when made in reference to acompound refers to a compound which is capable of reducing, delaying, oreliminating one or more undesirable pathologic effects in a subject.

As used herein, “interstitial cystitis” and “IC” refers to a progressivedisorder of the lower urinary tract that causes the symptoms of urinaryfrequency, urgency, and/or pelvic pain in a wide variety of patterns ofpresentation. An example of a recent review is Parsons, Clin ObstetGynecol, 45(1):242-249 (2002).

As used herein, “urinary frequency” refers to the number of urinationtimes per day.

As used herein, “urinary urgency” refers to refers to an inability todelay urination.

As used herein, “pelvic pain” refers to pain in the pelvic region ofgenital and non-genital origin and of organic or psychogenic aetiology.

As used herein, “urinate,” “urination,” “urinating,” “void” and“voiding” refers to release of urine from the bladder to the outside ofthe body.

As used herein, “urine” refers to a liquid waste product filtered fromthe blood by the kidneys, stored in the bladder and expelled from thebody through the urethra by the act of urinating.

As used herein, “oral,” and “by oral administration” refers to theintroduction of a pharmaceutical composition into a subject by way ofthe oral cavity (e.g. in aqueous liquid or solid form).

As used herein, “oral agent” refers to a compound that can beadministered by way of the oral cavity (e.g. in aqueous liquid or solidform). In one embodiment, an oral agent is a heparinoid (e.g. pentosanpolysulfate sodium (PPS)).

As used herein, “instill,” “instilled,” “instillation,” refers to one ormore of the following; to drop in, to pour in drop by drop, to impartgradually, to infuse slowly, to cause to be imbibed, (e.g. exampleinfuse slowly an intravesical solution).

As used herein, “intravesical,” refers to inside the bladder. As such,“intravesical instillation,” “intravesical therapy,” “instill,” and“instillation” refers to solutions that are administered directly intothe bladder. In some embodiments, instillation is via catheterization.Further, “intravesical solution,” “intravesical agent,” “intravesicaltherapeutic,” and intravesical compound” refers to a treatment that canbe administered to the bladder. For example, in one embodiment, anintravesical agent is intravesical heparin. In another embodiment, anintravesical agent is PPS. In one embodiment, intravesical therapy is acombination of an oral and an intravesical agent. It is not intendedthat the present invention be limited to a combination of an oral and anintravesical agent. For example, in one embodiment, intravesical therapyis an intravesical agent. In another embodiment, intravesical therapy isa combination of intravesical agents.

As used herein, “extravesical” refers to outside the bladder.

As used herein, “cystoscopic examination” and “cystoscopy” refers to anexamination that uses a cytoscope.

As used herein, “cystoscope” refers to an endoscopic instrument tovisualize the lower urinary tract, that includes the bladder and theurethra.

As used herein, “urethra” refers to a tube draining the urine to theoutside. As used herein, “bladder” refers to a hollow muscular organthat stores urine until it is excreted from the body.

As used herein, the terms “subject” and “patient” refer to any animal,such as a mammal like a dog, cat, livestock, and a human (e.g. a humanwith a disease). In one embodiment, a patient has one or more of urinaryurgency, urinary frequency, pelvic pain, recurrent urinary tractinfections, dyspareunia, overactive bladder, dry, etc.).

As used herein, “urinary tract infections” refers to a condition thatincludes an inflamed urethra and painful urination. In some embodiments,a urinary tract infection is caused by bacteria. In some embodiments, aurinary tract infection is not caused by bacteria.

As used herein, “recurrent urinary tract infections” refers to frequentepisodes of urinary tract infections.

As used herein, “dyspareunia” refers to pain during intercourse.

As used herein, “overactive bladder” refers to a sudden involuntarycontraction of the muscular wall of the bladder causing urinary urgency,an immediate unstoppable need to urinate and a form of urinaryincontinence.

As used herein, “urinary incontinence” refers to the unintentional lossof urine and inability to control urination or prevent its leakage.

As used herein, “urinary continence” refers to a general ability tocontrol urination.

As used herein, “catheter” refers to a tube passed through the body fordraining fluids or injecting them into body cavities. It may be made ofelastic, elastic web, rubber, glass, metal, or plastic.

As used herein, “catheterization” refers to the insertion of a slendertube through the urethra or through the anterior abdominal wall into thebladder, urinary reservoir, or urinary conduit to allow urine drainage.

As used herein, “catheterized” refers to the collection of a specimen bya catheterization. The terms “sample” and “specimen” are used in theirbroadest sense and encompass samples or specimens obtained from anysource.

As used herein, the term “biological samples” refers to samples orspecimens obtained from animals (including humans), and encompassescells, fluids, solids, tissues, and gases. Biological samples includetissues (e.g., biopsy material), urine, cells, mucous, blood, and bloodproducts such as plasma, serum and the like. However, these examples arenot to be construed as limiting the types of samples which find use withthe present invention.

As used herein, the term “urine cytology” refers to an examination of aurine sample that is processed in the laboratory and examined under themicroscope by a pathologist who looks for the presence of abnormalcells.

As used herein, “urinary dysfunction” and “urinary tract dysfunction”refers to abnormal urination, patterns or bladder habits, includingwetting, dribbling and other urination control problems.

As used herein, “heparinoid” refers to any molecule comprising a“glycosaminoglycan” which refers to a molecule comprising a network oflong, branched chains of sugars (e.g. chondroitin sulphate, heparansulphate, hyaluronic acid, keratin sulphate, dermatan sulphate,hyaluronan and the like) and optimally further comprising smaller,nitrogen-containing molecules (e.g. low molecular weight molecules). Itis not meant to limit the present invention to any one glycosaminoglycan(GAG) or source of GAG. GAG molecules include but are not limited to lowmolecular weight (LMW) GAGs, naturally derived GAGS, biotechnologicallyprepared GAGS, chemically modified GAGS, synthetic GAGS, and the like.It is not meant to limit the present invention to any one heparinoidmolecule or source of heparinoid molecule. As used herein, “heparin”refers to a heterogeneous group of straight-chain anionicglycosaminoglycans, as described above, having anticoagulant propertieswith a molecular weight ranging from 2,000 to 40,000 Da. Heparin ismeasured by its specific anticoagulation activity in units.

As used herein, “anesthesia” refers to a loss of feeling or inability tofeel pain.

As used herein, “local anesthesia” refers to a method of pain preventionin a small area of the body.

As used herein, “low-molecular-weight heparins” refers to a lowermolecular weight (LMW) species ranging from 2,000-8,000 daltons (e.g.,pentosan polysulfate sodium ranging from 4,000-6,000 daltons).

As used herein, the phrases “pharmaceutically acceptable salts”, “apharmaceutically acceptable salt thereof” or “pharmaceutically acceptedcomplex” for the purposes of this application are equivalent and referto derivatives prepared from pharmaceutically acceptable non-toxic acidsor bases including inorganic acids and bases and organic acids andbases.

As used herein, “lower urinary epithelial dysfunction” refers todisorders with positive potassium sensitivity tests (e.g. IC,prostatitis and the like).

As used herein, “urinary dysfunction” refers to abnormal urination,patterns or bladder habits, including wetting, dribbling and otherurination control problems.

As used herein, “anticoagulant” refers to delaying or preventing bloodcoagulation. It is not meant to limit the types of sugars present on aheparin of the present invention. Five examples of sugars occurring inheparin are: (1) α-L-iduronic acid 2-sulfate, (2)2-deoxy-2-sulfamino-α-D-glucose 6-sulfate, (3) β-D-glucuronic acid, (4)2-acetamido-2-deoxy-α-D-glucose, and (5) α-L-iduronic acid. Heparin ismeasured by its specific anticoagulation activity in units.

As used herein, “buffer” refers to a chemical that neutralizes eitheracids or bases thus stabilizing pH (for example, sodium bicarbonate).

As used herein, “sodium bicarbonate” refers to a compound with theformula NaHCO.

As used herein, “base” and “basic solution” refers to a solution whoseaddition to a second solution aids in providing a specific pH for thecombined solution (for example, addition of a sodium bicarbonatesolution provides a pH of at least 8.0, as described herein).

As used herein, “normal saline” refers to solutions comprising varyingconcentrations of sodium chloride (NaCl) in water that are compatiblewith fluids in the body (e.g. solutions comprising 0.9% NaCl thatcompatible with the salinity found in most mammalian cells and in humanblood). Normal saline will range in pH depending upon the pH of thewater used in preparation (e.g. pH of water ranging from 5.5-8.5).

As used herein, “buffered normal saline” refers to a saline solutioncontaining a buffer in order to establish a specific pH value or range(e.g. buffered normal saline with a pH of 7.3 to 7.5 for compatibilitywith normal human blood). Saline solutions may further comprise sugars(e.g. glucose, dextrose and the like).

As used herein, the term “units” refers to specific activity inInternational Units (IU) and/or United States Pharmacopeia (USP) units.For example, in one embodiment, heparin contains at least 130 USP unitsper mg.

As used herein, “USP” unit refers to the quantity of heparin thatprevents 1.0 mL of citrated sheep plasma from clotting for 1 hour afterthe addition of 0.2 mL of 1% CaCl₂ at 20 degree C. when compared to aUSP reference standard (defined as units/mL).

As used herein, “IU” refers to the quantity of heparin that is active inassays as established by the Fifth International standard forUnfractionated Heparin (WHO-5) (defined as International Units/mL)(Linhardt, R. J. & Gunay, N. S. (1999) Semin Thromb Hemost 25, 5-16.).

In the experimental disclosure which follows, the followingabbreviations apply: M (molar); mM (millimolar); μM (micromolar); nM(nanomolar); mol (moles); mol (millimoles); μmol (micromoles); nmol(nanomoles); g (grams); mg (milligrams); μg (micrograms); pg(picograms); L (liters); mL (milliliters); ml (milliliters); μL(microliters); cm (centimeters); mm (millimeters); μm (micrometers); nm(nanometers); C (degrees Centigrade).

Compositions of the Invention

The compositions of the invention provide a combination of a heparinoid,an anesthetic agent, a buffering compound and, optionally, an osmolaragent, in the manufacture of pharmaceutical compositions for treatingIC.

In accordance with the practice of the invention, the composition may bein a solid state or in solution. Preferably, when in solution, thecomposition has a pH of between 7 and 12.

In one embodiment, the composition comprising a heparinoid, a localanesthetic agent, a buffering compound and an osmolar component are insolution and the osmolar component is present in a sufficient amount sothat the final solution is isotonic or near isotonic.

Heparinoid Component of the Compositions of the Invention

The heparinoid in the composition of the invention includes but is notlimited to any of heparin, pentosan polysulfate sodium, heparan sulfate,heparin sodium, hyaluronic acid, and chondroitin sulfate, or acombination thereof.

In some embodiments, a heparinoid comprises a heparin-like molecule(e.g. heparan sulfate). For example, a heparin-like molecule such asheparan sulfate is a glycoprotein with a structure similar to heparinwith the difference being that heparan sulfate has undergone lesspolymerization than heparin and so has more glucuronic acid and N-acetylglucosamine than heparin. Heparan sulfate contains fewer sulfate groups,so is not as effective as an anticoagulant as heparin. Heparin andheparan sulfate are both characterized by repeating units ofdisaccharides containing a uronic acid (glucuronic or iduronic acid) andglucosamine, which is either N-sulfated or N-acetylated. The sugarresidues may be further O-sulfated at the C-6 and C-3 positions of theglucosamine and the C-2 position of the uronic acid. There are at least32 potential unique disaccharide units in this class of compounds.

Particularly in severe IC, intravesical heparin can be used either aloneor in combination with PPS [Parsons, et al. Br J Urol 73:504-507 (1994);Ho, et al. Urology 53:1133-9 (1999)].

Intravesical instillations of hyaluronic acid, a glycosaminoglycanmarketed in Canada as Cystistat, may be of benefit for some IC patients.Clinical trials of hyaluronic acid are underway in the United States,but this compound is not approved for U.S. use. The present inventioncontemplates the substitution of hyaluronic acid for heparin.

In some embodiments, heparin is a higher molecular weight speciesranging from 8,000-40,000 daltons. As used herein, “low-molecular-weightheparins” refers to a lower molecular weight (LMW) species ranging from2,000-8,000 daltons (e.g., pentosan polysulfate sodium ranging from4,000-6,000 daltons. LMW heparins are made by enzymatic or chemicalcontrolled hydrolysis of unfractionated heparin and have very similarchemical structure as unfractionated heparin except for some changesthat may have been introduced due to the enzymatic or chemicaltreatment. While not intending to limit the mechanism of action of theinvention's compositions, the mechanism of action of these drugs may besimilar to that of full-length heparin. LMW heparins are usuallyisolated from bulk heparin.

In one embodiment, heparin or another heparinoid is a heparin salt (e.g.heparin sodium, pentosan polysulfate sodium, heparan sulfate, as inExample 1). As used herein, the phrases “pharmaceutically acceptablesalts”, “a pharmaceutically acceptable salt thereof” or“pharmaceutically accepted complex” for the purposes of this applicationare equivalent and refer to derivatives prepared from pharmaceuticallyacceptable non-toxic acids or bases including inorganic acids and basesand organic acids and bases. Since the compound of the present inventionis acidic, salts may be prepared from pharmaceutically acceptablenon-toxic bases. A suitable pharmaceutically acceptable counterion forthe heparin is a positively-charged counterion such as sodium, calcium,ammonium, and substituted ammonium.

The amount of the heparinoid in the compositions of the invention willvary depending on the subject, severity and course of the disease, thesubject's health and response to treatment and the judgment of thetreating physician. Accordingly, the dosages of the molecules should betitrated to the individual subject.

For example, for chronic therapy, intravesical heparin can be prescribedat a dose of 10,000-40,000 IU in 10 ml water daily. For maintenance,this same heparin and water solution can be instilled three timesweekly, typically on a Monday-Wednesday-Friday schedule [Parsons, et al.Br. J Urol 73:504-507 (1994)]. For immediate relief of IC pain andurgency, heparin can also be used in place of PPS in one embodiment foran intravesical therapeutic solution, which is described below.

For example, in one embodiment, heparin contains at least 130 USP unitsper mg. As used herein, “USP” unit refers to the quantity of heparinthat prevents 1.0 ml of citrated sheep plasma from clotting for 1 hourafter the addition of 0.2 ml of 1% CaCl₂ at 20 degree C. when comparedto a USP reference standard (defined as units/ml). As used herein, “IU”refers to the quantity of heparin that is active in assays asestablished by the Fifth International standard for UnfractionatedHeparin (WHO-5) (defined as International Units/ml) (Linhardt, R. J. &Gunay, N. S. (1999) Semin Thromb Hemost 25, 5-16.).

For example, Pentosan polysulfate sodium (PPS) may be given at a dose of300 mg per day, although a higher dose may be necessary to obtain asuccessful result in some cases. For example, for men with IC, PPS maybe prescribed at about 600 mg per day, in two or three divided doses.

In accordance with the practice of the invention, merely by way ofexample, when the heparinoid is heparin, the amount of heparinoid in thecomposition may be between about 0.5 mg to about 1000 mg of heparin perunit dose (for example about 500 units of heparin to about a maximum of100,000 units of heparin (e.g., about 1000 USP units to about 100,000USP units per dose or 100 USP units to about 600 USP units per unit doseof heparin)).

In accordance with the practice of the invention, merely by way ofexample, when the heparinoid is pentosan polysulfate sodium, the amountof heparinoid in the composition may be about 1 mg to about 600 mg ofpentosan polysulfate sodium per unit dose (for example about 100 mg toabout 600 mg per unit dose of pentosan polysulfate sodium).

In accordance with the practice of the invention, merely by way ofexample, when the heparinoid is heparan sulfate, the amount ofheparinoid in the composition may be about 0.5 mg to about 10,000 mg ofheparan sulfate per unit dose (for example about 100 mg to about 30 mgper unit dose of heparan sulfate).

In accordance with the practice of the invention, merely by way ofexample, when the heparinoid is hyaluronic acid, the amount ofheparinoid in the composition may be about 5 mg to about 600 mg ofhyaluronic acid per unit dose (for example about 10 mg to about 100 mgper unit dose of hyaluronic acid).

In accordance with the practice of the invention, merely by way ofexample, when the heparinoid is chondroitin sulfate, the amount ofheparinoid in the composition may be about 1 mg to about 10,000 mg ofchondroitin sulfate per unit dose (for example about 100 mg to about 300mg per unit dose of chondroitin sulfate).

In accordance with the practice of the invention, merely by way ofexample, when the heparinoid is heparin sodium, the amount of heparinoidin the composition may be about 10 mg to about 600 mg of heparin sodiumper unit dose.

In the embodiment of the invention, the patient maybe directed toadminister intravesical heparin 40,000 IU in 8 mL of 1% lidocaine and 3mL of sodium bicarbonate once to twice a day. In one embodiment, thissolution is used alone. In some embodiments, this solution is used incombination with PPS (e.g. particularly in cases of severe IC). In someembodiments, intravesical treatment can be added after 9 to 12 months oftreatment with oral PPS (e.g. for patients with moderate IC). In someembodiments, the patient administers intravesical heparin (40,000 units)in 8 mL of 1% lidocaine and 3 mL of sodium bicarbonate (see below) onceor twice a day (e.g. a combination therapy). In some embodiments, theintravesical medication usually can be tapered slowly and discontinued(e.g. when patients are responding well).

Anesthetic Component of the Compositions of the Invention

The anesthetic (e.g., the local anesthetic) in the compositions of theinvention includes but is not limited to any of benzocaine, lidocaine,tetracaine, bupivacaine, cocaine, etidocaine, flecamide, mepivacaine,pramoxine, prilocalne, procaine, chloroprocaine, oxyprocaine,proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine,chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine,levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, andpharmaceutically acceptable derivatives and bioisosteres thereof, or acombination thereof. Preferably, the anesthetic (e.g., local anesthetic)is selected from the group consisting of lidocaine, bupivicaine,benzocaine, tetracaine, etidocaine, flecamide, prilocalne, anddibucaine, or a combination thereof. In a preferred embodiment, thelocal anesthetic comprises at least one of lidocaine, bupivacaine, andmepivacaine. Most preferably, the local anesthetic is lidocaine. Theamount of the anesthetic in the compositions of the invention will varydepending on the subject, severity and course of the disease, thesubject's health and response to treatment and the judgment of thetreating physician. Accordingly, the dosages of the molecules should betitrated to the individual subject. For example, the amount ofanesthetic agent in the compositions may be in the range of about 10 mgto about 400 mg per unit dose. For example, the amount of lidocaine canbe 10 mL of 1% lidocaine per unit dose or 16 mL of 2% lidocaine per unitdose.

Buffering Compounds of the Compositions of the Invention

The buffering compounds in the compositions of the invention includesbut is not limited to bicarbonate buffer, THAM or Tris(Tris(hydroxymethyl)aminomethane) buffer, MOPS buffer(3-morpholino)propanesulfonic acid), HEPES(N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid) buffer, ACES(2-[(2-amino-2-oxoethyl)amino]ethanesulfonic acid) buffer, ADAN-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO(3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer,BES (N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid buffer, Bicine(N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris(bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS(3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO(3-(cyclohexylamino)-2-hydroxy-1-propanesulfonic acid) buffer, CHES(2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO(3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid)buffer, HEPPS(N-(2-hydroxyethylpiperazine)-N′-(3-propanesulfonic acid)buffer, HEPPSO(N-(2-hydroxyethyl)piperazine-N′-(2-hydroxypropanesulfonicacid) buffer, MES (2-(N-morpholino)ethanesulfonic acid) buffer,triethanolamine buffer, imidazole buffer, glycine buffer, ethanolaminebuffer, phosphate buffer, MOPSO(3-(N-morpholino)-2-hydroxypropanesulfonic acid) buffer, PIPES(piperazine-N,N′-bis(2-ethanesulfonic acid) buffer, POPSO(piperazine-N,N′-bis(2-hydroxypropanesulfonic acid) buffer, TAPSN-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer; TAPSO(3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid)buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid)buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer),2-amino-2-methyl-1,3-propanediol buffer, and 2-amino-2-methyl-1-propanolbuffer. In a preferred embodiment, the buffer is sodium bicarbonatebuffer, Tris buffer, phosphate buffer, MOPS buffer, and HEPES buffer, ora combination thereof. In a preferred embodiment, the buffering compoundcomprises at least one of sodium bicarbonate and THAM (tromethamine orTris hydroxymethylpropyl). More preferably, the buffering compound issodium bicarbonate. The amount of the buffering compound in thecompositions of the invention will vary depending on the subject,severity and course of the disease, the subject's health and response totreatment and the judgment of the treating physician. Accordingly, thedosages of the molecules should be titrated to the individual subject.For example, the amount of the buffering compound(s) in the compositionsof the invention is the amount sufficient to raise the pH of thecomposition to above about pH 7; preferably above pH 8; or in a rangebetween about pH 7-12. For example, the amount of sodium bicarbonate maybe about 3 mL of 8.4% sodium bicarbonate (w/v) per unit dose.

Osmolar Component of the Compositions of the Invention

The therapeutic composition may also contain an osmolar component thatprovides an isotonic or nearly isotonic solution compatible with humancells and blood. Typically the osmolar component is a salt, such assodium chloride, or a sugar or a combination of to or more of thesecomponents. The sugar may be a monosaccharide such as dextrose, adisaccharide such as sucrose or lactose, a polysaccharide such asdextran 40, dextran 60, or starch, or a sugar alcohol such as mannitol.It should be obvious to those skilled in the art that all components ofthe composition contribute to the osmolarity of the solution but toachieve an isotonic or near-isotonic solution, the contributions ofthese components should be taken into account to ensure that the properosmolar component is added and not added in excess which would result ina hypertonic solution.

Due to the inflamed, permeable nature of the urothelium, a preferredsolution would be isotonic or near isotonic. Hypotonic solutions areknown to result in cell lysis, particularly of red blood cells, butother cells may also be damaged leading to increased cell damage in thebladder and accessible underlying layers. Hypertonic solutions mayresult in cell shrinkage which may enlarge pores or weaken celljunctions allowing urinary solutes more access to underlying cell layersleading to further damage, pain and inflammation. The addition of anosmolar component to the composition to form an isotonic or nearisotonic solution ensures that neither of these two possibilities occur.Typically, the osmolar component is 0.9% sodium chloride, or somewhatless as the other components in the solution also contribute to thesolution's osmolarity and thus should be taken into account. Typicallythe osmolar component is a salt, such as sodium chloride, or a sugar ora combination of to or more of these components. The sugar may be amonosaccharide such as dextrose, a disaccharide such as sucrose orlactose, a polysaccharide such as dextran 40, dextran 60, or starch, ora sugar alcohol such as mannitol. It should be obvious to those skilledin the art that all components of the composition contribute to theosmolarity of the solution but to achieve an isotonic or near-isotonicsolution, the contributions of these components should be taken intoaccount to ensure that the proper osmolar component is added and notadded in excess which would result in a hypertonic solution.

The osmolar component of the compositions of the invention includes butis not limited to sodium chloride, dextrose, dextran 40, dextran 60,starch and mannitol, or a combination thereof.

The amount of the osmolar component in the compositions of the inventionwill vary depending on the subject, severity and course of the disease,the subject's health and response to treatment and the judgment of thetreating physician. Accordingly, the dosages of the molecules should betitrated to the individual subject. For example, the amount of theosmolar component(s) in the compositions of the invention is at least 50milliosmoles.

Additional embodiments of the invention include pharmaceuticalcompositions comprising the composition of the invention and apharmaceutically acceptable carrier.

Examples of suitable pharmaceutical carriers and adjuvants include anymaterial which when combined with the components of the compositions ofthe invention retain the component's activity, and is non-reactive withthe subject's immune system. These carriers and adjuvants include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, phosphatebuffered saline solution, water, emulsions (e.g. oil/water emulsion),salts or electrolytes such as, disodium hydrogen phosphate, sodiumchloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances and polyethylene glycol. Othercarriers may also include sterile solutions. Compositions comprisingsuch carriers are formulated by well known conventional methods. Suchcompositions may also be formulated within various lipid compositions,such as, for example, liposomes as well as in various polymericcompositions, such as polymer microspheres.

In a further embodiment, the present invention provides pharmaceuticalcompositions for inhibiting Interstitial Cystitis and its symptoms in asubject. In an embodiment, the pharmaceutical composition comprises aheparinoid, which composition may be administered together with apharmaceutical composition comprising a local anesthetic agent and apharmaceutical composition comprising a buffering compound andoptionally a pharmaceutical composition comprising an osmolar agent thatprovides an isotonic or nearly isotonic solution, for example,compatible with human cells and blood. The aforementioned pharmaceuticalcompositions may be administered concomitantly or in sequence.

In another embodiment, the order of administration of the heparinoid andthe local anesthetic agents can be switched such that the localanesthetic agent is administered with a heparinoid and a bufferingcompound and optionally an osmolar agent, or, the buffering compound isadministered with a local anesthetic agent and a heparinoid andoptionally an osmolar component. A description of the heparinoids, localanesthetic agents, buffering compounds and osmolar components aredetailed above.

In a further embodiment of the invention, the present invention provideskits (e.g., a packaged combination of reagents with instructions)containing the compositions of the invention or components of thecomposition of the invention useful for treating Interstitial Cystitisand/or the symptoms of IC. The kit may further comprise a labelindicating that the heparinoid, the anesthetic agent and the bufferingcompound are useful to treat Interstitial Cystitis.

The kit can contain a pharmaceutical composition that includes thecompositions of the invention, and an acceptable carrier or adjuvant,e.g., pharmaceutically acceptable buffer, such as phosphate-bufferedsaline, Ringer's solution and dextrose solution. It may further includeother materials desirable from a commercial and user standpoint,including other buffers, diluents, filters, needles, syringes, andpackage inserts with instructions for use. The composition may beprovided as dry powders, usually lyophilized, including excipients thatupon dissolving will provide a reagent solution having the appropriateconcentration.

The kit comprises a container with a label and/or instructions. Suitablecontainers include, for example, bottles, vials, and test tubes. Thecontainers can be formed from a variety of materials such as glass orplastic. The container can have a sterile access port (for example thecontainer can be an intravenous solution bag or a vial having a stopperpierceable by a needle such as a hypodermic injection needle). Thecontainer can hold the composition(s) of the invention for treating IC.

In another embodiment, the kit comprises multiple containers, one foreach of the components of the compositions of the invention and/or apharmaceutically acceptable buffer, such as phosphate-buffered saline,Ringer's solution and dextrose solution. It may further include othermaterials desirable from a commercial and user standpoint, includingother buffers, diluents, filters, needles, syringes, and package insertswith instructions for use.

The kit may also suitably include a label and/or instructions on, orassociated with the container. The label can provide directions forcarrying out the preparation of the components of the compositions ofthe invention, for example, dissolving of the dry powders, and/ortreatment for IC.

The label and/or the instructions can indicate directions for either invivo or in vitro use of the compositions or pharmaceutical compositionsof the invention. The label and/or the instructions can indicate thatthe composition or pharmaceutical composition is used alone, or incombination with other agents.

The label can indicate appropriate dosages for the molecules of theinvention. The label and/or the instructions can also indicate that thepharmaceutical composition can be used alone, or in combination, with aother agent to treat e.g., IC or the symptoms of IC.

In an embodiment, the present invention provides products (for examplekit-of-parts) containing a heparinoid, a local anesthetic agent, abuffering compound and optionally an osmolar component, as a combinedpreparation for simultaneous, separate or sequential use, in inhibitingInterstitial Cystitis and its symptoms in a subject.

Methods of the Invention

The invention also provides methods for inhibiting Interstitial Cystitisin a subject. The method comprises administering an effective amount ofthe compositions of the invention to the subject to inhibit IC and itssymptoms in the subject. In accordance with the foregoing, the presentinvention provides in a yet further aspect methods as defined abovecomprising co-administration, e.g. concomitantly or in sequence, of atherapeutically effective amount of a heparinoid, a local anestheticagent, and a buffering compound or a heparinoid, a local anestheticagent, a buffering compound, and an osmolar component in free form or inpharmaceutically acceptable salt form to inhibit IC and its symptoms inthe subject. The composition may be administered in solid state or insolution. Administration may be effected by any of the following means:intravesicular administration, administration by means of biodegradablepolymers, administration by means of hydrogels, and administrationthrough dual chamber syringes.

A description of the heparinoids, anesthetics, buffering compounds andosmolar components is detailed above.

The most effective mode of administration and dosage regimen for thecompositions of the present invention depends upon the seventy andcourse of the disease, the subjects health and response to treatment andthe judgment of the treating physician. Accordingly, the dosages of themolecules should be titrated to the individual subject.

Adjustments in the dosage regimen may be made to optimize the ICinhibiting response. Doses may be divided and administered on a dailybasis or the dose may be reduced proportionally depending upon thesituation. For example, several divided doses may be administered dailyor the dose may be proportionally reduced as indicated by the specifictherapeutic situation.

Merely by way of example, the amount of heparinoid may be between about0.5 mg to about 1000 mg of heparin per unit dose (for example about 1000USP units to about 100,000 USP units per dose or 100 USP units to about600 USP units per unit dose of heparin), about 1 mg to about 600 mg ofpentosan polysulfate sodium per unit dose (for example about 100 mg toabout 600 mg per unit dose of pentosan polysulfate sodium), about 0.5 mgto about 10,000 mg of heparan sulfate per unit dose (for example about100 mg to about 30 mg per unit dose of heparan sulfate), about 5 mg toabout 600 mg of hyaluronic acid per unit dose (for example about 10 mgto about 100 mg per unit dose of hyaluronic acid), about 1 mg to about10,000 mg of chondroitin sulfate per unit dose (for example about 100 mgto about 300 mg per unit dose of chondroitin sulfate), or about 10 mg toabout 600 mg of heparin sodium per unit dose. Additional dosages may befound supra. It would be clear to one skilled in the art that dosagewill vary depending on the particular heparinoid being used.

The description of the local anesthetic is detailed above. An attendingphysician will determine specific dosages of the local anesthetic foreach subject. The amount of lidocaine may be 10 mL of 1% lidocaine perunit dose or 16 mL of 2% lidocaine per unit dose. Additional dosages maybe found supra. The amount of local anesthetic will vary depending onthe local anesthetic being used.

The description of the buffering compound is detailed above. The sodiumbicarbonate may be 3 mL of 8.4% sodium bicarbonate (w/v) per unit dose.Additional dosages may be found supra. Since the buffering compoundincreases the absorbance of the local anesthetic agent, the amount ofbuffering compound will vary depending on the buffering compound and thelocal anesthetic agent being used.

The description of the osmolar component is detailed above. Dosages maybe found supra. An attending physician will determine specific dosagesof the osmolar component for each subject. The osmolar component ispresent in a sufficient amount so that the final solution is isotonic ornear isotonic.

Pentosan polysulfate sodium may be formulated for oral administrationand may be administered in a quantity from about 100 mg/day to about 600mg/day or in a quantity from about 100 mg/day to about 300 mg/day.Additional dosages may be found supra.

In accordance with the foregoing, the present invention provides methodsfor repairing a mucin layer of bladder tissue thereby inhibitingInterstitial Cystitis. The method comprising co-administration, e.g.concomitantly or in sequence, of a therapeutically effective amount ofheparinoid, local anesthetic agent, buffering compound and osmolarcomponent or the compositions of the invention.

The subjects treated by the present invention include mammaliansubjects, including, human, monkey, ape, dog, cat, cow, horse, goat,pig, rabbit, mouse and rat.

In accordance with the foregoing, the present invention provides methodsfor monitoring the course of Interstitial Cystitis in a subjectcomprising intravesicular administration of a solution containing anamount of potassium that would elicit pain in a subject that has acompromised urothelium and monitoring their pain response at differentpoints in time, a difference in the amount of pain determined beingindicative of the course of the Interstitial Cystitis condition, whereinthe subject has been administered any of the compositions of theinvention.

In another embodiment, the method for monitoring comprisesquantitatively determining in a first sample of a biological fluid fromthe subject the amount of potassium and comparing the amount sodetermined with the amount present in a second sample from the subject,such samples being taken at different points in time, a difference inthe amounts determined being indicative of the course of theInterstitial Cystitis condition, wherein the subject has beenadministered the compositions of the invention.

In accordance with the practice of the invention, examples of heparinoidinclude but are not limited to heparin, pentosan polysulfate sodium,heparan sulfate, hyaluronic acid, chondroitin sulfate and heparinsodium, or a combination thereof; examples of anesthetic agent includebut are not limited to lidocaine, bupivacaine, and mepivacaine, or acombination thereof; examples of buffering compound include but are notlimited to bicarbonate and THAM (tromethamine or Trishydroxymethylpropyl), or a combination thereof and suitable examples ofan osmolar component include but are not limited to sodium chloride,dextrose, dextran 40, dextran 60, starch and mannitol, or a combinationthereof.

In a further aspect of the above uses, the heparinoid, anesthetic agent,buffering compound and osmolar agent can be administered concomitantlyor in sequence.

A description of the amounts of the heparinoid, anesthetic agent,buffering compound and osmolar agent is provided supra. An attendingphysician may determine specific dosages of the heparinoid, anestheticagent, buffering compound and osmolar agent, for each subject.

ADVANTAGES OF THE INVENTION

The available data indicate that the size of the potential market forthe compounds used in the multimodal IC treatment approach is quitelarge. The most current estimate of the true prevalence of IC is thatthe disease affects as many as 1 in 4.5 women [Parsons, et al. Urology60:573-578 (2002)] and 1 in 20 men [Nickel, et al. J Urol. 165:842-845(2001)] in the United States. In our extensive clinical experience, themultimodal treatment regimen is effective in up to 85-90% of cases ofIC. The current prevalence estimates come from true prevalence studiesin which a general population was screened for the characteristicsymptom complex of IC. Previous prevalence studies have focused onscreening a population for individuals who have already received adiagnosis of IC, and have used diagnostic criteria that recognized onlythe fraction of the IC patient population that has severe, advanceddisease.

The number of identified cases of IC is likely to grow substantially asmore and more clinicians recognize IC as the actual cause in patientswhose symptoms initially had been attributed to other problems.

Until recently, the diagnosis of IC was based on criteria, originallydeveloped for research purposes, (Gillenwater and Wein, J Urol140(1):203-206 (1988)) which describe the relatively rare case ofadvanced disease. A case of IC usually was not recognized until it wasquite severe and had produced bladder lesions that could be seen bycystoscopic examination. As knowledge about IC has grown, the medicalcommunity has become much better able to detect mild or moderatedisease, which responds to available therapies in most cases.

In IC, the goal of therapy is to achieve control of the disease symptomswhile addressing the underlying cause(s) of the disorder. The inventionresolves symptoms of pain and urgency by neural desensitization by e.g.,the alkalinized lidocaine—the underlying urothelium integrity isimproved by the heparin sodium.

The following examples serve to illustrate certain embodiments andaspects of the present invention and are not to be construed as limingthe scope thereof.

EXAMPLE 1

The IC treatment approach described under Current Practice belowrepresents a therapeutic paradigm of the present invention for IC/LUDE.This paradigm reflects a volume of research and clinical data that hasrevolutionized our concept of IC pathogenesis, diagnosis, and treatmentin recent years. Traditionally considered rare and difficult to manage,IC is now known to be relatively common and highly treatable.

Recognizing IC

Until recently, the diagnosis of IC was based on criteria, originallydeveloped for research purposes, (Gillenwater and Wein, J Urol140(1):203-206 (1988)) which describe the relatively rare case ofadvanced disease. A case of IC usually was not recognized until it wasquite severe and had produced bladder lesions that could be seen bycystoscopic examination. As used herein, “cystoscopic examination” and“cystoscopy” refers to an examination that uses a cytoscope. As usedherein, “cystoscope” refers to an endoscopic instrument to visualize thelower urinary tact that includes the bladder and the urethra. As usedherein, “urethra” refers to a tube draining the urine to the outside. Asused herein, “bladder” refers to a hollow muscular organ that storesurine until it is excreted from the body. As knowledge about IC hasgrown, the medical community has become much better able to detect mildor moderate disease, which responds to available therapies in mostcases.

The diagnosis of IC is relatively simple if the clinician takes thefollowing approach: look for the characteristic pattern of IC symptoms(Table 1) in the appropriate clinical setting, rule out other definablecauses of the patient's urgency/frequency and/or pelvic pain and rely onthe potassium sensitivity test (PST; described below) to confirm thediagnosis.

The symptoms of IC tend to occur in a pattern of sudden flares followedby remissions, with the flares becoming more severe and more continuousas the disease progresses. Moderate to severe IC can severely impair apatient's physical, emotional, social, and professional life. Severalclinical situations should alert the physician that IC might be present.One example is women with recurrent urinary tract infections. Usuallythese episodes are IC flares, as shown by negative urine cultures.Another example are women or men with dyspareunia; most will have IC.Another example is women with a diagnosis of “overactive bladder, dry.”Most likely, these patients have IC. As used herein, the terms “subject”and “patient” refer to any animal, such as a mammal like a dog, cat,livestock, and a human (e.g. a human with a disease). In one embodiment,a patient has one or more of urinary urgency, urinary frequency, pelvicpain, recurrent urinary tract infections, dyspareunia, overactivebladder, dry, etc. As used herein, “urinary tract infections” refers toa condition that includes an inflamed urethra and painful urination. Insome embodiments, a urinary tract infection is caused by bacteria.

In some embodiments, a urinary tract infection is not caused bybacteria. As used herein, “recurrent urinary tract infections” refers tofrequent episodes of urinary tract infections. As used herein,“dyspareunia” refers to pain during intercourse. As used herein,“overactive bladder” refers to a sudden involuntary contraction of themuscular wall of the bladder causing urinary urgency, an immediateunstoppable need to urinate and a form of urinary incontinence. As usedherein, “urinary incontinence” refers to the unintentional loss of urineand inability to control urination or prevent its leakage. As usedherein, “urinary continence” refers to a general ability to controlurination.

Urgency/frequency is not always present in an individual with IC. Evenif a patient urinates more than 8 times in 24 hours, the frequency mayhave developed so gradually that he or she has not recognized it asabnormal. A 24-hour voiding log or the Pelvic Pain and Urgency/Frequency(PUF) Scale (described in the following section) or both are useful inobtaining a true picture of the patient's voiding patterns.

The pain of IC, rather than symptoms of urgency/frequency, is whatusually brings a patient to the doctor. The location of the pain is whatguides the patient to choose either a urologist or a gynecologist.Unfortunately, the pain does not necessarily point to the origin of theproblem, which is the lower urinary tract. A patient with IC mayperceive the pain anywhere in the pelvis, in 1 or more locations in anycombination (Table 1). IC pain often includes pain during or immediatelyafter sexual intercourse. A number of factors can influence the severityof a patient's symptoms on any given day (Table 2). Thus, IC isextremely variable in its presentation; its symptoms can be mistaken forsigns of a different urologic or gynecologic problem. However, it isimportant to detect this condition because effective therapy isavailable, and early cases respond more readily to treatment than doadvanced cases.

Diagnostic Tools

IC should be suspected in any man or woman who presents with urinaryurgency/frequency and/or pelvic pain in the absence of any otherdefinable cause. Several simple diagnostic tools can help the clinicianrule out other causes of the patient's complaints and establish thelikelihood of the presence of IC.

Rule Out Other Problems

A simple urinalysis, and a urine culture if indicated, are the onlytests required to rule out most other problems that should be consideredin a patient with the symptoms of IC. A voided urine specimen should beobtained for analysis. Because patients with IC often void low volumes,if the voided specimen is not negative, it is optimal to obtain acatheterized urine specimen for analysis (Brendler, In: Walsh, et al,eds., Campbell's Urology, 7th ed. Philadelphia, Pa.: WB Saunders Co; 144(1998)). An IC patient's catheterized specimen should show no bacteriaand probably will show no red or white blood cells. As used herein,“catheter” refers to a tube passed through the body for draining fluidsor injecting them into body cavities. It may be made of elastic, elasticweb, rubber, glass, metal, or plastic. As used herein, “catheterization”refers to the insertion of a slender tube through the urethra or throughthe anterior abdominal wall into the bladder, urinary reservoir, orurinary conduit to allow urine drainage. As used herein, “catheterized”refers to the collection of a specimen by a catheterization. The terms“sample” and “specimen” are used in their broadest sense and encompasssamples or specimens obtained from any source. As used herein, the term“biological samples” refers to samples or specimens obtained fromanimals (including humans), and encompasses cells, fluids, solids,tissues, and gases. Biological samples include tissues (e.g., biopsymaterial), urine, cells, mucous, blood, and blood products such asplasma, serum and the like. However, these examples are not to beconstrued as limiting the types of samples which find use with thepresent invention.

If urinalysis reveals gross or microscopic hematuria, the presence ofmalignancy should be ruled out via a complete urologic workup. Any maleover age 40 should undergo a urine cytology and an office cystoscopy.Individuals who are at high risk for cancer should be identified andevaluated according to standard urologic practice. As used herein, theterm “urine cytology” refers to an examination of a urine sample that isprocessed in the laboratory and examined under the microscope by apathologist who looks for the presence of abnormal cells.

PUF Scale

The questionnaire of the present invention is designed to elicit abalanced picture of a patient's IC symptoms (FIG. 1). It has beenvalidated in both urologic and gynecologic patients with pelvic pain,most of whom were determined to have IC (Parsons, et al. Urology60(4):573-578 (2002)). There appears to be a strong correlation betweena patient's PUF score and his or her chance of having a positive resulton the PST (FIG. 1). The PUF Scale is useful in screening male andfemale patients for the presence of IC symptoms. The higher the PUFscore, the greater the likelihood that the patient has IC (Table 3).

Potassium Sensitivity Test

The intravesical PST, which can be performed in a clinician's office, isuseful in establishing the diagnosis of IC (Parsons, et al. NeurourolUrodyn 13(5):515-520 (1994); Parsons, et al. J Urol 159(6):1862-1867(1998); Parsons, et al. Urology 59(3):329-333 (2002)). A number ofrecent studies indicate that the PST is a sensitive and reliableindicator of the presence of the disease (Parsons, et al. NeurourolUrodyn 13(5):515-520 (1994); Parsons, et al. J Urol 159(6):1862-1867(1998); Parsons et al. Urology 59(3):329-333 (2002); Parsons and Albo, JUrol 168(3):1054-1057 (2002)).

The PST detects a lower urinary tract dysfunction that appears to bepresent in most individuals with IC (Parsons, et al. J Urol145(4):732-735 (1991). As used herein, “urinary dysfunction” and“urinary tract dysfunction” refers to abnormal urination, patterns orbladder habits, including wetting, dribbling and other urination controlproblems. This dysfunction of the epithelial defense mechanisms resultsin an abnormally permeable epithelium that fails to protect theunderlying tissues from potentially damaging substances in the urine;chiefly, potassium. If urinary potassium is allowed to penetrate theepithelium, it can depolarize nerves and muscle and cause the symptomsof urinary urgency or pain (or both) as well as tissue damage (Parsonset al. J Urol 159(6):1862-1867 (1998)).

For the PST, two separate solutions, sterile water and potassiumchloride are instilled via a catheter into the patient's bladder(Parsons, et al. Urology 2002; 59(3):329-333). An individual with normalbladder epithelial defense mechanisms experiences no symptoms inresponse to the potassium solution. However, in a person with anabnormally permeable epithelium, the potassium solution provokessymptoms of urgency or pain or both. FIG. 2 provides instructions forperforming the PST.

The patient uses a numeric analog scale to grade any pain or urgencythat results from the instillation of each solution. After bothsolutions have been instilled, the patient is asked to indicate whichsolution caused more severe symptoms. If the patient's urgency or paingrade is at least 2 points above 0 and the patient indicated that thepotassium solution provoked more severe symptoms, the PST result ispositive.

IC is a Common Disorder

Although IC originally was believed to be rare, the latest data suggestthat it is quite common. The earliest prevalence data reflected thetraditional IC diagnostic criteria (Gillenwater, et al. J Urol 1988;140(1):203-206 (1987)) and probably excluded all but advanced cases ofthe disease. In 1999, prevalence in the United States was estimated at750,000 cases (Curhan, et al. J Urol 161(2):549-552 (1999)). Even thismore recent figure does not reflect the true prevalence of IC because itincludes only diagnosed cases. It probably does not include most mild tomoderate cases, which go undetected or are mistaken for other problems.

Prevalence in Women

In a study reported last year, gynecologists from several clinicalpractices in the United States found strong evidence that there arelarge numbers of unrecognized cases of IC among their chronic pelvicpain (CPP) patients (Parsons, et al. Obstet Gynecol 98(1):127-132(2001); Parsons, et al. Am J Obstet Gynecol 187(5):1395-1400 (2002). Therate of positive PST results among 114 pelvic pain patients was 85%(Parsons, et al. Obstet Gynecol 98(1):127-132 (2001)). These findingswere confirmed in a larger follow-up study with controls, in which thePST result was positive in 198 (81%) of 244 pelvic pain patients and innone of the controls. As the size of the nation's CPP patient populationhas been estimated at 9 million women or more, (Mathias, et al. ObstetGynecol 87(3):321-327 (1996)) these findings suggest that the number ofIC patients may be at least 10 times higher than the estimate publishedin the most recent epidemiologic study (Curhan, et al. J Urol161(2):549-552 (1999). If this is the case, at least 7 million women inthe United States may have IC. The data showing a high prevalence of ICwere further corroborated by the results of a study in which a samplepopulation of women was surveyed using the PUF Scale (Parsons, et al.Urology 60(4):573-578 (2002)). In this study, 1 of every 4 women had aPUF score that predicted the presence of IC.

Prevalence in Men

Findings from two recent studies suggest that unsuspected numbers ofmale patients have IC, (Parsons and Albo, J Urol 168(3):1054-1057(2002); Bernie, et al. J Urol 166(1):158-161 (2001)). PST results werepositive in 37 (84%) of 44 men who had been diagnosed with prostatitis(Parsons and Albo, J Urol 168(3):1054-1057 (2002)) and in 84 (16%) of526 men who were undergoing urodynamic evaluation for possible bladderoutlet obstruction due to benign prostatic hyperplasia (Bernie, et al. JUrol 166(1):158-161 (2001)). In the latter study, the PST-positive menalso demonstrated urodynamics results similar to those characteristic ofIC.

Treatment

Most patients with IC will benefit from a three-part plan for medicaltreatment (Table 4) that focuses on the following: restoring lowerurinary tract epithelial function with heparinoid therapy; reversingneural activation with tricyclic antidepressant therapy; and controllingallergies with antihistamine therapy.

Once other disorders have been ruled out (as described in the previoussection), treatment should not be withheld from a patient who has signsand symptoms of IC but who has negative results from the intravesicalPST. If the physician's clinical impression is that a patient has IC,the patient should be started on IC therapy as described here.

Restoring Lower Urinary Tract Epithelial Function

For most IC patients, the cornerstone of treatment comprises aheparinoid therapy with oral pentosan polysulfate sodium (Parsons, etal. J Urol 150(3):845-848 (1993); Mulholland, et al. Urology35(6):552-558 (1990); Parsons and Mulholland, J Urol. 138(3):513-516(1987); Holm-Bentzen, et al. J Urol 138(3):503-507 (1987); Hanno,Urology 49 (5A suppl):93-99 (1997); Nickel, et al. J Urol 165 (suppl5):67 Abstract 273, (2001)) (PPS; ELM ON, Ortho-McNeil/Alza),intravesical heparin, (Parsons, et al. Br J Urol 73(5):504-507 (1994))or both. Heparinoids are similar in structure to the glycosaminoglycansin the bladder surface mucus and are believed to help repair or restorethe epithelium (Parsons, Urology 49 (5A suppl):100-104 (1997) inindividuals who have abnormal epithelial permeability. As used herein,“heparinoid” refers to any molecule comprising a “glycosaminoglycan”which refers to a molecule comprising a network of long, branched chainsof sugars (e.g. chondroitin sulphate, heparan sulphate, hyaluronic acid,keratin sulphate, dermatan sulphate, hyaluronan and the like) andoptimally further comprising smaller, nitrogen-containing molecules(e.g. low molecular weight molecules). Glycosaminoglycan also refers to“mucopolysaccharide.” It is not meant to limit the present invention toany one glycosaminoglycan (GAG) or source of GAG. GAG molecules includebut are not limited to low molecular weight (LMW) GAGs, naturallyderived GAGS, biotechnologically prepared GAGS, chemically modifiedGAGS, synthetic GAGS, and the like. It is not meant to limit the presentinvention to salts (e.g. sodium sale, calcium salt and the like) andsulfates and includes other forms of these molecules. It is not meant tolimit the present invention to any one heparinoid molecule or source ofheparinoid molecule. In some embodiments, a heparinoid comprises aheparin-like molecule (e.g. heparan sulfate). For example, aheparin-like molecule such as heparan sulfate is a glycoprotein with astructure similar to heparin with the difference being that heparan hasundergone less polymerization than heparin and so has more glucuronicacid and N-acetyl glucosamine than heparin. Heparan contains fewersulfate groups, so is not as effective as an anticoagulant as heparin.Heparin and heparan sulfate are both characterized by repeating units ofdisaccharides containing a uronic acid (glucuronic or iduronic acid) andglucosamine, which is either N-sulfated or N-acetylated. The sugarresidues may be further O-sulfated at the C-6 and C-3 positions of theglucosamine and the C-2 position of the uronic acid. There are at least32 potential unique disaccharide units in this class of compounds. Insome embodiments, a heparinoid comprises a heparin molecule (e.g. aheparin sodium), a pentosan polysulfate sodium (PPS) and the like. Asused herein, “heparin” refers to a heterogeneous group of straight-chainanionic glycosaminoglycans, as described above, having anticoagulantproperties with a molecular weight ranging from 2,000 to 40,000 Da.

In some embodiments, heparin is a higher molecular weight speciesranging from 8,000-40,000 daltons. As used herein, “low-molecular-weightheparins” refers to a lower molecular weight (LMW) species ranging from2,000-8,000 daltons (e.g., pentosan polysulfate sodium ranging from4,000-6,000 daltons. LMW heparins are made by enzymatic or chemicalcontrolled hydrolysis of unfractionated heparin and have very similarchemical structure as unfractionated heparin except for some changesthat may have been introduced due to the enzymatic or chemicaltreatment. While not intending to limit the mechanism of action of theinvention's compositions, it is the inventor's view that mechanism ofaction of these drugs is similar to that of full-length heparin. LMWheparins are usually isolated from bulk heparin. In one embodiment,heparin is a heparin salt (e.g. heparin sodium, pentosan polysulfatesodium, heparan sulfate). As used herein, the phrases “pharmaceuticallyacceptable salts”, “a pharmaceutically acceptable salt thereof” or“pharmaceutically accepted complex” for the purposes of this applicationare equivalent and refer to derivatives prepared from pharmaceuticallyacceptable non-toxic acids or bases including inorganic acids and basesand organic acids and bases. Since the compound of the present inventionis acidic, salts may be prepared from pharmaceutically acceptablenon-toxic acids. A suitable pharmaceutically acceptable counterion forthe heparin is a positively-charged counterion such as sodium, calcium,ammonium, and substituted ammonium.

Recent data indicate that PPS is the most effective treatment availablefor IC (Hanno, Urology 49 (5A suppl):93-99 (1997); Nickel et al. J Urol165 (suppl 5):67. Abstract 273 (2001). These longitudinal open-labelstudies have shown that the response rate increases with increasingduration of treatment, reaching approximately 70% after 8 to 12 monthsof therapy (Hanno, Urology 49 (5A suppl):93-99 (1997); Nickel et al. JUrol 165 (suppl 5):67. Abstract 273, (2001)) PPS typically is given at adose of 300 mg per day, although a higher dose may be necessary toobtain a successful result in some cases. For men with IC, PPS, 600 mgper day, (off-label use), in two or three divided doses is routinelyprescribed. It should be noted that prescribing PPS at a dose above 300mg/day is an off-label use of the drug.

In the embodiment of the invention, the patient is directed toadminister intravesical heparin 40,000 IU in 8 mL, 1% lidocaine, and 3mL of sodium bicarbonate once to twice a day. In one embodiment, thissolution is used alone. In some embodiments, this solution is used incombination with PPS (e.g. particularly in cases of severe IC). In someembodiments, intravesical treatment can be added after 9 to 12 months oftreatment with oral PPS (e.g. for patients with moderate IC). In someembodiments, the patient administers intravesical heparin (40,000 units)in 8 mL of 1% lidocaine and 3 mL of sodium bicarbonate (see below) onceor twice a day (e.g. a combination therapy). In some embodiments, theintravesical medication usually can be tapered slowly and discontinued(e.g. when patients are responding well).

Symptoms of urgency and pain can persist in an IC patient after theepithelium has been restored because it takes time for upregulatedbladder nerves to deactivate. The results of heparinoid therapy shouldbe judged only after at least 1 year of treatment in a patient with mildto moderate disease and only after at least 2 years of treatment in apatient with severe IC.

Treatment for Immediate Relief of Symptoms

Encouraging data were obtained from a preliminary study of anintravesical solution for the immediate and sustained relief of thesymptoms of urgency and pain in IC patients. The solution contains40,000 units of heparin or 100 mg PPS, 80 mg of lidocaine, and 3 mL ofsodium bicarbonate (see below) in a total fluid volume of 15 mL. Theabsorption of the lidocaine is increased by the presence of the sodiumbicarbonate, which is the principal difference between the therapeuticsolution of the present invention and other similar solutions that havebeen tried.

In the preliminary study, 31 (78%) of 40 patients experiencedsignificant immediate relief of their IC symptoms. Of the patients whoused the solution 3 to 7 times weekly for 2 weeks or more, 85% hadsustained pain relief. If further studies confirm these promisinginitial results, this solution will be the first treatment to offerimmediate relief of the pain and urgency of IC.

Goal of Therapy

In IC, the goal of therapy is to achieve control of the disease symptomswhile addressing the underlying cause(s) of the disorder. The inventionresolves symptoms of pain and urgency by neural desensitization by thealkalinized lidocaine—the underlying urothelium integrity is improved bythe heparin sodium. With the guidance of the physician, the patientshould make his or her own treatment decisions. In the treatmentprocess, it is important for the clinician to help the patient developan understanding of what to expect from the disease and from thetreatment over the long term. Many IC patients have suffered for yearsbefore finding a physician who recognizes the source of their symptoms.

Achieving Control of Symptoms

The IC symptoms of frequency, urgency, and pelvic pain presentdifferently among patients who have IC, and can vary from one day to thenext in a single affected individual. IC is a progressive disorder thattends to present as a series of flares and remissions in its earlystages. Typically, IC symptoms do not become both severe and continuousuntil the disease has been present for many years [Parsons, et al.Urology 57:428-33 (2001); Hand, J Urol 61:291-310 (1949); Parsons,Neurourol Urodyn 9:241-50 (1990); and Koziol, et al. J Urol 149:465-9(1993)].

A patient may perceive IC pain as dysuria and/or as pain in thesuprapubic area, the lower abdomen, the lower back, the medial thighs,the inguinal area, the urethra, the vagina or vulva in women, and thescrotum or testes in men [Parsons, et al. Urology 57:428-33 (2001);Hand, J Urol 61:291-310 (1949)]. A given patient may experience pain inone or more of these locations, in any combination. Recent studiessuggest there are significant numbers of IC patients in the populationsof men and women who seek treatment for chronic pelvic pain [Parsons, etal. Urology 60:573-578 (2002); Parsons, et al. Am. J. Obstet Gynecol187:1395-1400 (2002); Parsons and Albo, J Urol 168:1054-1057 (2002)].Approximately 3 out of 4 IC patients, both male and female, have painassociated with sexual activity. Pain may be the patient's only symptomof IC, as some IC patients experience no urinary urgency/frequency. Inmy clinical experience, a female patient who has dyspareunia and chronicpelvic pain has an 80% chance of having a genitourinary source for thatpain, regardless of where in the pelvis the pain is perceived.

It is well known that a number of factors provoke flares of IC symptomsin affected individuals. These include hormonal fluctuations, theactivity of seasonal allergies, physical stress, emotional stress, andsexual activity [Parsons, et al. Urology 57:428-33 (2001); Parsons,Neurourol Urodyn 9:241-250 (1990); Koziol, Urol Clin North Am. 21:7-71(1994); Held, et al. in Interstitial Cystitis, Hanno, et al (Eds),Springer-Verlag, London, p: 29-48 (1990)]. In addition, a patient'ssymptoms will depend on the lower urinary tract tissues affected by thedisease. There is increasing evidence that IC is part of a largerdisorder that can be called Lower Urinary Dysfunctional Epithelium(LUDE) [Parsons, et al. Urology 57:428-33 (2001); Parsons, et al.Urology 60:573-578 (2002); Parsons, et al. Am J Obstet Gynecol187:1395-1400 (2002); Parsons and Albo, J Urol 168:1054-1057 (2002)].LUDE can affect the bladder, the urethra, and (in men) the prostate. Forall of these reasons, it is more accurate to regard IC as a continuumthan as a disease with a single, characteristic clinical presentation.

In the effort to provide symptom relief for the IC patient, an importantfirst step is to identify and quantify all of the IC symptoms from whichthe patient currently suffers. A recently validated IC symptomquestionnaire of the present invention, the Pelvic Pain andUrgency/Frequency Patient Symptom Scale (PUF Scale, FIG. 1) can beextremely useful for this purpose [Parsons, et al. Urology 60:573-578(2002)]. The PUF Scale is a self-administered questionnaire that can becompleted by the patient in less than 5 minutes. It contains questionsthat elicit and quantify urinary frequency and/or urgency (if any),pelvic pain, and/or pain associated with sexual activity. The result isa single numeric score from 0 through 35. The higher the PUF score, thegreater the likelihood that the individual has IC [Parsons, et al.Urology 60:573-578 (2002)]; for this reason, the PUF can be useful indistinguishing IC from other disorders during the process of diagnosis.

A patient's responses on the PUF Scale also may make the clinician awareof any IC symptoms the patient may experience but may not recognize asabnormal. Individuals who have urinary frequency (that is, voiding 8 ormore times per day) may not report it as a problem because it has alwaysbeen normal for them, or does not worry them. Nevertheless, it is asymptom that indicates the presence of a pathophysiologic process thatmust be recognized so that treatment can be initiated as early aspossible in the disease process. Frequency is typically the firstsymptom to appear in an individual who has IC. Urinary urgency oftenfollows, and pain tends to be a later manifestation of the disease. Inclinical experience, pain—especially acute pain—usually is the symptomthat prompts the patient to seek treatment for IC.

Addressing an Underlying Cause of IC

Bladder epithelial permeability and urinary potassium appear to play akey role in the development of many cases of the disease [Parsons, etal. J Urol 159:1862-1867 (1998)]. In the healthy bladder, a mucus layercontaining glycosaminoglycans (GAGs) forms a barrier that prevents urineand its contents from leaking through the urothelium and damaging theunderlying nerves and muscle [Lilly and Parsons, Surg Gynecol Obstet171:493-496 (1990)]. Most individuals with IC have an epithelialdysfunction that renders the urothelium abnormally permeable. As aresult, potentially harmful substances in urine are allowed to leakthrough the epithelium and penetrate the bladder muscle. Potassium,which occurs in high concentrations in normal urine, does not damage orpenetrate a healthy urothelium but is highly toxic to tissues such asthe bladder muscularis. The depolarization of sensory nerves in thebladder muscle by potassium could produce the symptoms of IC as well ascause its progression.

A growing body of data supports this hypothesis. On the basis of thismodel of IC pathogenesis, the Potassium Sensitivity Test (PST) wasdeveloped to test for the presence of abnormal bladder epithelialpermeability. Although use of the PST is not yet generally accepted, anumber of centers around the world have reported results of more than2200 PSTs performed on IC patients [Parsons, et al. Urology 57:428-33(2001), Parsons and Albo, J Urol 168:1054-1057 (2002); Koziol, Urol ClinNorth Am 21:7-71 (1994); Held, et al. in Interstitial Cystitis, Hanno,et al (Eds), Springer-Verlag, London, p: 29-48 (1990); Parsons, et al.Neurourol Urodyn 3:515-520 (1994); Payne and Browning, J Urol 155(Suppl):438A (1996); Parsons, et al. J Urol 159:1862-1867 (1998);Chambers, et al. J Urol 162:699-701 (1999); Teichman and Nielson-Omeis,J Urol 161:1791-1794 (1999); Chen, et al. J Urol 165 (Suppl.):67 (2001);Daha, et al. J Urol 165 (Suppl):68 (2001); Forrest and Vo, Urology 57(Suppl 6A):26-29 (2001); Kuo, Formos Med Assoc 100:309-314 (2001);Grégoire, et al. J Urol 168:556-557 (2002); Parsons, et al. Urology59:329-333 (2002)]. The PST has been positive in 78% of those ICpatients tested, providing considerable evidence most IC patients have aurothelial permeability defect, and that a positive PST is a validindicator of the presence of IC [Parsons, et al. Urology 57:428-33(2001); Parsons and Albo, J Urol 168:1054-1057 (2002); Koziol, Urol ClinNorth Am 21:7-71 (1994); Held, et al. in Interstitial Cystitis, Hanno,et al (Eds), Springer-Verlag, London, p: 29-48 (1990); Parsons, et al.Neurourol Urodyn 3:515-520 (1994); Payne and Browning, J Urol 155(Suppl):438A (1996); Parsons, et al. J Urol 159:1862-1867 (1998);Chambers, et al J Urol 162:699-701 (1999); Teichman and Nielson-Omeis, JUrol 161:1791-1794 (1999); Chen, et al. J Urol 165 (Suppl.):67 (2001);Daha, et al. J Urol 165 (Suppl):68 (2001); Forrest and Vo, Urology 57(Suppl 6A):26-29 (2001); Kuo, Formos Med Assoc 100:309-314 (2001);Grégoire, et al. J Urol 168:556-557 (2002); Parsons, et al. Urology59:329-333 (2002); Kuo, Urol Int 71:61-65 (2003)].

The epithelial permeability defect model of IC pathogenesis is therationale for medical treatment of IC with heparinoid compounds, whichare described in the next section. Investigators have documentedincreased mast cell activity and neurological upregulation in ICpatients. Although the precise role of these processes in ICpathophysiology is not clear, both increased mast cell activity andneurological upregulation may contribute to the generation of ICsymptoms in the lower urinary tract. Addressing the increased mast cellactivity and neurological upregulation with oral hydroxyzine andamitriptyline, respectively, has proved to be helpful to many ICpatients in our clinical practice.

IC is a relatively common disorder that may affect more than 7 millionwomen in the United States as well as a surprising number of men. Thegold standard for diagnosis of IC is clinical: the disease can bedetected from the characteristic pattern of IC symptoms in theappropriate clinical setting and in the absence of other definablecauses, which usually can be ruled out with urine analysis. Tools suchas the PUF scale and the PST are useful in establishing the diagnosis ofIC. The majority of patients with this condition can be treatedsuccessfully using a 3-part program to restore epithelial function,inhibit neural activation, and control allergies.

This treatment method addresses lower urinary epithelial dysfunction, afactor that appears to play a role in many cases of IC. As used herein,“lower urinary epithelial dysfunction” refers to disorders with positivepotassium sensitivity tests (e.g. IC, prostatitis and the like). As usedherein, “urinary dysfunction” refers to abnormal urination, patterns orbladder habits, including wetting, dribbling and other urination controlproblems. Using this treatment method, the clinician can provide bothimmediate and long-term control of symptoms while treating theunderlying cause of the disease for the majority of IC patients.

The present invention focuses on treatment for the patients who make upthe majority of the IC population, who have IC symptoms and are notcurrently receiving therapy for their disease. However it is not meantto limit the treatment to untreated IC patents nor to IC patients withtypical symptoms and is meant to include those at either extreme whohave mild symptoms and those with severe and debilitating IC, eventhough such cases of the latter are relatively rare. The presentinvention is not meant to limit the treatment to IC patients and ismeant to include those patients with positive potassium sensitivitytests that would likely benefit from the treatment (e.g. prostatitis andthe like).

Available Compounds Heparinoid Compounds

For the majority of cases of IC, the cornerstone of treatment isheparinoid therapy. In some embodiments, compounds used for this purposecomprise intravesical heparin [Parsons, et al. Br J Urol 73:504-507(1994); Ho, et al. Urology 53:1133-9 (1999)]. In some embodiments,compounds used for this purpose comprise oral pentosan polysulfatesodium (PPS) [Parsons, et al. J Urol 150:845-848 (1993); Mulholland, etal. Urology 35:552-558 (1990); Parsons, et al. J Urol 138:513-516(1987); Holm-Bentzen, et al. J Urol 138:503-507 (1987); Hanno, Urology49 (Suppl 5A):93-99 (1997); Nickel, et al. J Urol 165 (5 Suppl):67(2001)].

Oral Pentosan Polysulfate Sodium (PPS)

Pentosan polysulfate sodium (PPS), whose structure is similar to that ofthe GAGs in the lower urinary tract, appears to allow the restoration ofthe urothelial mucus layer [Parsons, et al. Urology 59:329-333 (2002);Parsons, Urology 49 (Suppl. 5A):100-104 (1997)]. PPS is the onlyFDA-approved oral medication for treating IC in the United States (e.g.Pentosan polysulfate sodium (ELMIRON)). It is currently the mosteffective IC treatment available [Hanno, Urology 49 (Suppl 5A):93-99(1997); Nickel, et al. J Urol 165 (5 Suppl):67 (2001)], as well as themost rigorously tested in clinical trials. Data from longitudinalstudies in open phase have shown that the rate of response to PPSincreases with the duration of treatment, reaching approximately 70%after 8-12 months of therapy [Hanno, Urology 49 (Suppl 5A):93-99 (1997);Nickel, et al. J Urol 165 (5 Suppl):67 (2001)].

Intravesical Heparin

Particularly in severe IC, intravesical heparin can be used either aloneor in combination with PPS [Parsons, et al. Br J Urol 73:504-507 (1994);Ho, et al. Urology 53:1133-9 (1999)]. For chronic therapy, intravesicalheparin can be prescribed at a dose of 10,000-40,000 IU in 10 ml waterdaily. For maintenance, this same heparin and water solution can beinstilled three times weekly, typically on a Monday-Wednesday-Fridayschedule [Parsons, et al. Br. J. Urol 73:504-507 (1994)]. For immediaterelief of IC pain and urgency, heparin can also be used in place of PPSin one embodiment for an intravesical therapeutic solution, which isdescribed below.

Intravesical instillations of hyaluronic acid, a glycosaminoglycanmarketed in Canada as Cystistat, may be of benefit for some IC patients.Clinical trials of hyaluronic acid are underway in the United States,but this compound is not approved for U.S. use.

The present invention contemplates the substitution of hyaluronic acidfor heparin (described below).

EXAMPLE 2 Current Practice

Most patients who have IC/LUDE will benefit from multimodal medicaltreatment based on heparinoid therapy. As an adjunct to this regimen, aprogram of intravesical therapy can be beneficial in providingimmediate, temporary symptom relief to patients whose disease is moresevere or long standing. The multimodal oral treatment regimen for IChas three parts (FIG. 6): heparinoid therapy to restore lower urinarytract epithelial function, tricyclic antidepressant therapy to inhibitneural activation, antihistamine therapy to control any allergies.

Once other causes have been ruled out, a patient who has signs andsymptoms of IC should be started on the treatment regimen describedhere. If it is the physician's clinical impression that the patient hasIC, IC treatment should not be withheld on the basis of a negative PSTand/or negative findings on cystoscopy.

Restoring Lower Urinary Tract Epithelial Function

In some embodiments, PPS is given at 300 mg/day in two or three divideddoses. In some embodiments, a higher dose is used. For example, PPS isgiven at 600 mg day in two or three divided doses for male IC patients.

In some embodiments, intravesical therapy is used either alone or incombination with PPS. A patient who has severe IC can supplement an oralPPS regimen with intravesical therapy instillations performed daily ortwice daily. The recommended solution contains heparin 40,000 IU in 10mL 1% lidocaine (w/v) (or 16 mL 2% lidocaine if 1% is not effective) and3 ml of sodium bicarbonate (see below). The sodium bicarbonate promotesabsorption of the lidocaine [Henry, et al. J Urol 165:1900-1903 (2001)].In most cases, the intravesical therapy can be tapered slowly and thendiscontinued as the patient's symptoms improve. As used herein,“anesthetic” refers to a class of medication that blocks the sensationof pain. As used herein, “local anesthetic” refers to a class ofmedication that temporarily stops the sensation of pain in a particulararea of the body. It is not meant to limit the specific local anestheticand can include one or more of the following: benzocaine, lidocaine,tetracaine, bupivacaine, cocaine, etidocaine, flecamide, mepivacaine,pramoxine, prilocalne, procaine, chloroprocaine, oxyprocaine,proparacaine, ropivacaine, dyclonine, dibucaine, propoxycaine,chloroxylenol, cinchocaine, dexivacaine, diamocaine, hexylcaine,levobupivacaine, propoxycaine, pyrrocaine, risocaine, rodocaine, andpharmaceutically acceptable derivatives and bioisosteres thereof.Preferably, the local anesthetic is selected from the group consistingof lidocaine, bupivicaine, benzocaine, tetracaine, etidocaine,flecamide, prilocalne, and dibucaine. Generic formulations of thesecompounds, mixtures containing these compounds, salt formulations ofthese compounds and the like. In some embodiments, a local anesthetic isa lidocaine (e.g. Example 2 and 3). Local anesthetics include mixturesof local anesthetics (e.g. lidocaine and prilocalne).

Because it may take time for upregulated nerves in the lower urinarytract to deactivate, an IC patient's symptoms of urgency and pain canpersist after heparinoid therapy has restored the urothelium. For thesereasons, the clinician should assess the results of heparinoid therapyonly after at least a year of treatment in cases of mild to moderatedisease, and only after at least two years of treatment in a case ofsevere IC. In general, if a patient does not appear to be responding toheparinoid therapy, adding other treatments to the regimen rather thandiscontinuing the heparinoid therapy is recommended.

Intravesical Treatment for Immediate Relief of Symptoms

Data from preliminary studies for one embodiment of an intravesicaltherapeutic solution can provide immediate temporary relief of thesymptoms of urgency and pain in IC “patients [Dell and Parsons, Abstractpresented at NIDDK/Interstitial Cystitis Association Symposium, ResearchInsights into Interstitial Cystitis, Alexandria, Va., (Oct. 30-Nov. 1,2003); Davis, et al. Abstract presented at NIDDK/Interstitial CystitisAssociation Symposium, Research Insights into Interstitial Cystitis,Alexandria, Va. (Oct. 30-Nov. 1, 2003); Parsons, Contemp Urol 15: 22-24,27-28, 31-32, 35 (2003)]. One of the methods of the present inventioncombines heparin and lidocaine buffered with sodium bicarbonate topH >8.0 via direct catheter delivery to the bladder, providing immediateand long term pain relief for chronic IC sufferers. In some embodiments,the solution contains 10,000-40,000 units of heparin. In someembodiments, heparin is replaced by 100-200 mg PPS (the contents of anoral capsule dissolved in 10 mL buffered normal saline), 10 mL 1%lidocaine or 16 mL 2% lidocaine, and 3 mL 8.4% sodium bicarbonate (w/v).The solution is instilled into the empty bladder and retained forapproximately 30 minutes. The principal difference between thistherapeutic solution and other such solutions is the presence of sodiumbicarbonate, which dramatically increases the absorption of thelidocaine. In one preliminary study using PPS, 41 of 55 patients (75%)experienced significant immediate relief of their IC symptoms. Use ofthe solution 3-7 times weekly for two weeks or more resulted insustained pain relief in 85% of patients [Parsons and Davis, PracticeBuilding Today September: 18-22 (2003)].

EXAMPLE 3

At the start of the study, each patient underwent intravesicalinstillation of a therapeutic solution composed of 40,000 U heparin, 8mL of 1% lidocaine (80 mg; group 1), and 3 mL of 8.4% sodium bicarbonatesuspended in a volume of 15 mL total fluid. After 47 patients had beentreated with one instillation of this solution, and no adverse events orside effects had developed, it was decided to increase the amount oflidocaine in the solution. Subsequently, all subjects received thismodified solution, which was identical to the original solution, exceptthat it contained 8 mL of 2% lidocaine (160 mg; group 2). All patientswere evaluated for pain and urgency relief within 20 minutes of thesingle instillation. Group 2 patients were evaluated by telephonefollow-up 24 to 48 hours after the instillation to determine theduration of their relief. In addition, group 2 patients who elected toreceive additional instillations of the 2% lidocaine solution wereevaluated to determine whether the efficacy of the solution persistedafter a course of three treatments per week for 2 weeks. All patientswere evaluated using the Patient Overall Rating of Improvement ofSymptoms scale (FIG. 9) on which they rated their symptoms of pain andurgency as “worse” or from “no better” (0% improvement) to “symptomsgone” (100% improvement) in 25% increments. Significant symptom reliefwas defined as a 50% or greater improvement in symptoms.

A total of 82 subjects were evaluated, 47 in group 1 and 35 in group 2.The mean patient age was 35 years (range 22 to 65). After oneinstillation, significant immediate relief of both pain and urgency wasobtained in 35 (75%) of 47 subjects who received the 1%lidocaine/heparin/sodium bicarbonate solution (group 1) and in 33 (94%)of 35 who received the 2% lidocaine/heparin sodium bicarbonate solution(group 2). The difference in the response rates between groups 1 and 2was statistically significant (P<0.01; chi-square analysis).Twenty-eight patients in group 2 were available for the evaluation ofthe duration of relief by telephone follow-up 24 to 48 hours after thesingle instillation. One half of these patients experienced at least 4hours of symptom relief from the instillation (FIG. 10). Twenty patientsin group 2 agreed to receive a course of three instillations per weekfor 2 weeks. Of the 20 patients, 16 (80%) reported significant sustainedrelief of pain and urgency. In all subjects, the symptom relief lastedfor at least 48 hours after the last intravesical treatment.

In addition to the safety and efficacy indicated by the preliminarydata, the intravesical therapeutic solution has several advantages.Patients can be taught to self-administer the instillations at home.Heparin and PPS appear to have equal efficacy in the therapeuticsolution; PPS offers the advantage of significantly lower cost. Inaddition, the solution can provide a therapeutic option for patients whoare unable to take the oral form of PPS.

Other Adjunct Therapies

In cases of severe IC or disease that is refractory to more conservativemanagement, patients may benefit from the use of implantableneurostimulators. Referral to a pain clinic for chronic pain managementmay also be helpful.

Other Factors

In a small percentage of cases, a factor that can affect the choice oftherapy within the multimodal IC treatment regimen is the patient'sability to tolerate oral PPS. If a patient receiving oral PPS has signsof gastrointestinal distress, or if the patient feels otherwise unableto take the oral PPS, the PPS can be administered via the intravesicaltherapeutic solution described above. This alternative bypasses the oralroute of administration and the accompanying potential for drug sideeffects. It is also less expensive than oral PPS treatment.

CONCLUSIONS

IC is a relatively common disorder that may affect as many as 1 in 4.5women [Parsons, et al. Urology 60:573-578 (2002)] and 1 in 20 men[Nickel, et al. J Urol 165:842-845 (2001)]. The disease can readily bedetected from the characteristic pattern of its symptoms in theappropriate clinical setting and in the absence of other definablecauses. In establishing the diagnosis, tools such as the PUF Scale andthe PST are useful. The majority of cases of IC can be treatedsuccessfully using a multimodal program of therapy directed at restoringlower urinary epithelial function, reversing neural activation, andcontrolling any allergies. In severe or long-standing cases of IC anintravesical treatment program can be an important adjunct that providesboth immediate and long-term symptom relief (Table 5 and 6, i.e. FIGS. 7and 8, respectively).

Throughout this application various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which the invention pertains.

1. A composition comprising: (i) heparin, (ii) a local anesthetic agent,and (iii) a buffering compound, wherein said heparin is present in aquantity from about 1000 USP units to about 100,000 USP units per unitdose.
 2. The composition of claim 1, additionally comprising an osmolarcomponent.
 3. The composition of claim 2, wherein the composition is insolution and the osmolar component is present in a sufficient amount sothat the final solution is isotonic or near isotonic.
 4. The compositionof claim 2, wherein the osmolar component comprises at least onecompound selected from the group consisting of sodium chloride,dextrose, dextran 40, dextran 60, starch and mannitol.
 5. Thecomposition of claim 1, wherein said local anesthetic agent is selectedfrom the group consisting of lidocaine, bupivacaine, and mepivacaine. 6.The composition of claim 5, wherein said local anesthetic agent islidocaine.
 7. The composition of claim 6, wherein said lidocaine isadded to said composition in the quantity of 10 mg up to 400 mglidocaine per unit dose.
 8. The composition of claim 1, wherein thebuffering compound comprises at least one of sodium bicarbonate and THAM(tromethamine or Tris hydroxy methylpropyl).
 9. The composition of claim8, wherein the buffering compound comprises sodium bicarbonate.
 10. Thecomposition of claim 9 wherein said sodium bicarbonate is added to saidcomposition in a quantity of about 3 ml of 8.4% sodium bicarbonate (w/v)per unit dose.
 11. The composition of claim 1, wherein the compositionis in a solid state.
 12. The composition of claim 1, wherein thecomposition is in solution.
 13. A composition comprising: (i) aheparinoid, (ii) a local anesthetic agent, and (iii) a bufferingcompound, wherein the composition has a pH from about 8 to about
 12. 14.A composition consisting essentially of: (i) a heparinoid, (ii) a localanesthetic agent, (iii) a buffering compound, and (iv) optionally anosmolar component, wherein the composition has a pH from about 7 toabout
 12. 15. A composition comprising a heparinoid component, a localanesthetic agent, and a buffering compound, wherein said heparinoidcomponent comprises at least one heparinoid selected from the listconsisting of: (i) heparin in the quantity of about 0.5 milligrams toabout 1000 milligrams per unit dose; (ii) pentosan polysulfate sodium inthe quantity of about 1 milligram to about 600 milligrams per unit dose;(iii) heparan sulfate in the quantity of about 0.5 milligrams to about10,000 milligrams per unit dose; (iv) hyaluronic acid in the quantity ofabout 5 milligrams to about 600 milligrams per unit dose; (v)chondroitin sulfate in the quantity of about 1 milligram to about 10,000milligrams per unit dose; and (vi) heparin sodium in the quantity ofabout 10 milligrams to about 600 milligrams per unit dose.
 16. Thecomposition of claim 15, wherein said heparinoid component comprisesheparin in the quantity of about 0.5 milligrams to about 1000 milligramsper unit dose.
 17. The composition of claim 15, wherein said heparinoidcomponent comprises pentosan polysulfate sodium in the quantity of about1 milligram to about 600 milligrams per unit dose.
 18. The compositionof claim 15, wherein said heparinoid component comprises heparan sulfatein the quantity of about 0.5 milligrams to about 10,000 milligrams perunit dose.
 19. The composition of claim 15, wherein said heparinoidcomponent comprises hyaluronic acid in the quantity of about 5milligrams to about 600 milligrams per unit dose.
 20. The composition ofclaim 15, wherein said heparinoid component comprises chondroitinsulfate in the quantity of about 1 milligram to about 10,000 milligramsper unit dose.
 21. The composition of claim 15, wherein said heparinoidcomponent comprises heparin sodium in the quantity of about 10milligrams to about 600 milligrams per unit dose.
 22. A compositioncomprising: (i) heparin, (ii) a local anesthetic agent, (iii) abuffering compound, and (iv) a pharmaceutically acceptable carriertherefore, wherein said heparin is present in a quantity from about 1000USP units to about 100,000 USP units per unit dose.